Scientists Are Smuggling Large Drugs Into the Brain—Opening a New World of Possible Therapies

Our brain is a fortress. Its delicate interior is completely surrounded by a protective wall called the blood-brain barrier.

True to its name, the barrier separates contents in the blood and the brain. It keeps bacteria and other pathogens in the blood away from delicate brain tissue, while allowing oxygen and some nutrients to flow through.

The protection comes at a cost: Some medications, made up of large molecules, can’t enter the brain. These include antibodies that block the formation of protein clumps in Alzheimer’s disease, immunotherapies that destroy deadly brain tumors, and missing enzymes that could rescue inherited developmental diseases.

For decades, scientists have tried to smuggle these larger drugs into the brain without damaging the barrier. Now, thanks to a new crop of molecular shuttles, they’re on the brink of success. A top contender is based on transferrin, a protein that supplies iron to the brain—an element needed for myriad critical chemical reactions to ensure healthy brain function.

Although still in its infancy, the shuttle has already changed lives. One example is Hunter syndrome, a rare and incurable genetic disease in which brain cells lack a crucial enzyme. Kids with the syndrome begin losing their language, hearing, and movement as young toddlers. In severe cases, their lives are tragically cut short at 10 to 20 years of age.

Early results in clinical trials using the transferrin shuttle are showing promise. After delivering the missing enzyme into the brains of kids and adults with Hunter syndrome with a shot into a vein, the patients gradually regained their ability to speak, walk, and run around. Without the shuttle, the enzyme is too big to pass through the blood-brain barrier.

If the shuttle passes further safety testing and can be adapted for different cargo, it could potentially ferry a wide range of large biotherapeutics—including gene therapies—directly into the brain with a simple jab in the arm. From cancer to neurodegenerative disorders and other common brain diseases such as stroke, it would open a new world of therapeutic possibilities.

Hitching a Ride

We often talk about the body and the brain as separate entities. In a way, they are. The blood-brain barrier, a tightly woven sheet of cells that lines vessels throughout the brain, regulates which molecules can enter. The cells are built like a brick wall—the molecules holding them together are literally called “tight junctions.”

But they’re not impenetrable. Small molecules, such as oxygen and caffeine can drift past the barrier, giving us that morning hit of energy with a good cup of coffee. Once inside the brain, these molecules can easily spread throughout the organ to feed energy-hungry tissues. Other molecules, such as glucose (sugar) or iron, require special protein “transporters” dotted along the surfaces of the barrier cells to enter.

Transporters are very specific about their cargo and can usually only grab onto one type of molecule. Once loaded up, the proteins pull the molecule into the interior of barrier cells by forming a fatty bubble around it, like a spaceship. The ship drifts across the barrier—with cargo protected inside—and releases its contents into the brain. In other words, it’s possible to temporarily open the barrier and transport larger molecules from the blood to the brain.

Some clever ideas are already being tested.

One of these is inspired by viruses that naturally infect the brain, such as HIV. After examining HIV’s protein sequence, scientists found a short—and safe—section called TAT that helps the virus tunnel through the barrier. Using protein sequencing, they can then physically tag small peptides (just a dozen or so protein “letters” long) to the TAT shuttle. Clinical trials are already underway using the system to reduce damage from stroke with just an injection. But the tiny carrier struggles with larger proteins such as antibodies or enzymes.

More recently, scientists took a hint from the transport mechanisms already embedded in the barrier—that is, why and how it allows some larger proteins in. The idea came from trials for Alzheimer’s disease. Breaking up the protein clumps characteristic of the disease with antibodies has shown promise in slowing symptoms, but they’re hard to deliver into the brain with an intravenous shot.

In most cases, roughly 0.1 percent of the treatment actually penetrates the brain, meaning that much higher doses are needed, adding expense and increasing the risk of side effects. The antibodies also crowd around blood vessels inside the brain rather than moving deeper.  

Iron Shuttle

One transporter, in particular, caught scientists’ eyes: transferrin. This large protein—picture a four-leaf clover—captures iron in the blood and then attaches itself to the barrier. Transferrin’s “stem” acts like a beacon, telling the barrier the cargo is safe to be shuttled into the brain. Barrier cells encapsulate transferrin for the voyage across and release it on the other side.

Rather than trying to engineer the entire protein, scientists synthesized only its stem—the most important part—which can then be connected to almost any large cargo. Multiple studies have found that the shuttle is relatively safe and doesn’t jeopardize normal iron processing in the brain. Cargos retained their function after the journey and once inside the brain.

Across the Divide

Transferrin-based shuttles are being investigated for a wide range of brain disorders.

In Hunter syndrome, a shuttle carrying a missing enzyme has shown early success. The therapy is effective, in part, because the shuttles end up inside a cell’s waste factories, or lysosomes. These acid-filled pouches are natural parking spots for the shuttle and its cargo—they’re also where the enzyme needs to go, making the condition a perfect use case.

Scientists are also eyeing other brain disorders such as Alzheimer’s disease, in which toxic clumps of a protein called amyloid beta gradually build up inside the brain. A shuttle could increase the number of therapeutic antibodies accessing the brain, making the therapy more efficient. Other teams are testing the method as way to carry cancer-destroying antibodies that target brain cancer stemming from metastasized breast cancer.

It’s still early days for these brain shuttles, but efforts are underway to engineer other blood-brain barrier transporters into carriers too. These have different properties compared to transferrin-based ones. Some release their cargo more slowly, for example, making them potentially useful for slow-release drugs with longer therapeutic effects.

Shuttles that can carry gene therapies or gene editors could also change how we treat inherited neurological diseases. Transferrin-based shuttles have already carried antisense oligonucleotides—molecules that block gene function—into the brains of mice and macaque monkeys and delivered functional CRISPR components into mice.

With increasingly powerful AI models that can predict and dream up protein sequences, researchers could further develop more efficient protein shuttles based on natural ones—massively expanding what’s possible for treating brain diseases.